Mono- and bis-[(1-piperidyl)-loweralkyl]amines



United States Patent 3,325,500 MONO- AND BIS-[(1-PIPERIDYL)-LOWER- ALKYL]AMINES Bernard L. Zenitz, Colonie, and Alexander R. Surrey, Albany, N.Y., assignors to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 15, 1965, Ser. No. 432,845 Claims. (Cl. 260-294) This application is a continuation-impart of our prior application Ser. No. 129,995, filed Aug. 8, 1961, and now abandoned.

This invention relates to primary, secondary, and tertiary (l-piperidyl)-loWer-alkylamines, their acid-addition salts, and to processes for the preparation thereof.

Said amines have utility as chemotherapeutic and pharmacodynamic agents of a nature to be more fully described hereinafter. The primary and secondary amines have further utility as intermediates in the preparation of certain 2- and 4-[(l-piperidyl)-loWer-alkylamin-o]quinolines, and 2- and 4-{N,N-bis-[(l-piperidyD-lower alkyl] amino} quinolines which are described and claimed in our copending parent application S.N. 129,995, filed Aug. 8, 1961, of which the instant application is a continuationin-part.

The compounds of the instant invention are represented by the formula:

R 5g salm.

a J in wherein R is a member of the group consisting of unsubstituted-carbamyl, N-lower-alkylcarbamyl, N,N-di-loweralkylcarbamyl, piperidinocarbonyl, pyrrolidinocarbonyl, hydroxy, hydroxy-lower-alkyl, lower-alkanoylamino, phenyl-lower-alkyl, and cyclo-alkyl-lower-alkyl; R is a member of the group consisting of hydrogen and from one to five lower-alkyl radicals; R is a member of the group consisting of hydrogen, benzoyl, benzyl, phenyllower-alkanoyl, phenyl-lower-alkyl, lower-alkanoyl, halolower-alkanoyl, lower-alkyl, cycloalkanecarbonyl, cycloalkyl-lower-alkanoyl, cycloalkyl-lower-alkyl, car-boxycycloalkylcarbonyl, hydroxymethyl-cycloalkylmethyl, phenoxy-lower-alkanoyl, phenoxy-lower-alkyl, phenyl-loweralkenoyl, carboxy-lower-alkanoyl, carbamyl, N-loweri.e., 1,2-ethylene, 1,4-butylene, 1-6-hexylene, and the like, or dicarbamylbiphenyl, i.e.,

alkylcarbamyl, N-cycloalkyl-carbamyl, N,N-di-loweralkylcarbamyl, N- phenylcarbarnyl, piperidinocarbonyl, pyrrolidinocarbonyl, thiocarbamyl, N-lower-alkylthiocarbamyl, N,N-di-lower-alkylthiocarbamyl, N-phenylthiocarbamyl, piperidinothiocarbonyl, pyrrolidinothiocarbonyl, hydroXy-lower-alkyl, cyano-lower-alkyl, phenylsulfonyl, amidino, amidoXimino-lower-alkyl, and loweralkyl-ketolower-alkanoylg Y is l0wer-alkylene containing from two to eight carbon atoms and interposing at least two carbon atoms between the amino nitrogen atom of the (l-piperidyl)-lower-alkylamino group and the ring nitrogen atom of the piperidine nucleus; and n is the integers 1 and 2, the third valence on the amino nitrogen atom being attached to a hydrogen atom when n is 1. The variable R in the compounds of Formula I above can also be a divalent radical joining two of the groupings:

The compounds of Formula I where R, is a hydrogen atom are useful as intermediates for the preparation of 2- and 4-[(l-piperidyl)-1ower-a1kylamino]quinolines and 2- and 4-{N,N-bis-[(l-piperidyl)-lower-alkyl]amino} quinolines having the formulas:

IFLYQR] Ila where R is a member of the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine, and iodine), lower-all oxy, hydroxy, monocarbocyclic aryllower alkoxy, trifluoromethyl, lower alkylmercapto, lower-alkylsulfinyl, and lower-alkylsulfonyl, and R R Y, and n have the meanings given above. The preparation of the compounds of Formulas 11a and Ilb from the compounds of Formula I is effected by reacting the com pounds of Formula I where R, is a hydrogen atom with a 2- or 4-haloquinoline. The reaction is carried out at a temperature in the range from about C. to about C. and can be carried out either with or without the use of a solvent. Suitable solvents are those that are inert under the conditions of the reaction, for example, lower-alkanols, e.g., methanol or isopropanol, and phenol. A preferred solvent is phenol.

In the above Formula I, when R is hydroXy or loweralkanoylamino, said radicals can occupy either the 3- or 4-positions of the piperidine ring. When R is unsubstituted-carbarnyl, N-lower-alkylcarbamyl, N,N-di-loweralkylcarbamyl, piperidinocarbonyl, pyrrolidinocarbonyl, hydroxy-lower-alkyl, phenyl-lower-alkyl, or cycloalkyllower-alkyl, said radicals can occupy any of the three available positions on the piperidine ring.

When R or R is hydroxy-lower-alkyl, the said group can be straight or branched and can contain from one to about six carbon atoms. R and R thus stand, inter alia, for hydroxymethyl, l-hydroxyethyl, 2-hydroxyethyl, 3- hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, S-hydroxypentyl, 6-hydroxyheXyl, and the like.

When R is lower-alkanoylamino or when R; is loweralkanoyl or halo-lower-alkanoyl, the lower-alkanoyl portion of said radicals can be either straight or branched and can contain from one to about six carbon atoms. R thus also stands, inter alia, for forrnylamino, acetylamino,

3 propionylamino, u-ethylbutyrylamino, and the like, and R stands, inter alia, for formyl, acetyl, Ot-ChlOIORCBtYl, Otbromoacetyl, a,a-dichloroacetyl, propionyl, tit-chloropropionyl, butyryl, oc-ChlOI'OblltYfYl, and the like.

When R or R is N-lower-alkylcarbamyl or N,N-dilower-alkylcarbamyl, or when R; is N-lower-alkylthiocarbamyl or N,N-di-lower-alkylthiocarbamyl, the alkyl moiety in each of said radicals can contain from one to about four carbon atoms and can be either straight or branched. Thus R and R also stand, inter alia, for N-methylcarbamyl, N-ethylcarbamyl, N-butylcarbamyl, N,N-dimethylcarbamyl, N,N-diethylcarbamyl, N,N-dibutylcarbamyl, and R stands, inter alia, for N-methylthioearbamyl, N- ethylthiocarbamyl, N-butylthiocarbamyl, N,N-dimethylthiocarbamyl, N,N-diethylthiocarbamyl, N,N-dibutylthiocarbamyl, and the like.

When R or R is phenyl-lower-alkyl or when R, is benzoyl, benzyl, phenyl-lower-alkanoyl, phenylloweralkenoyl, N phenylcarbamyl, N phenylthiocarbamyl, phenylsulfonyl, phenoxy-lower-alkanoyl, or phenoxyloWer-alkyl, the benzene ring thereof can be unsubstituted or can bear one or more substituents of low molecular weight and of such nature that they do not interfere with or take part in the reaction. Examples of such substituents include loWer-alkyl, halo, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfonyl, trifluoromethyl, sulfamoyl, methylenedioxy, benzyloxy, nitro, cyano, carboxy, hydroxy, lower-alkanoyloxy, lower-alkanoylamino, amino, di-loWer-alkanoylamino, and the like.

When R or R is phenyl-lower-alkyl, or when R is pehnoxy-lower-alkyl, phenoXy-loWer-alkanoyl, phenyllower-alkanoyl, or phenyl-lower-alkenoyl, the lower-alkyl or lower-alkanoyl moieties thereof contain from one to five carbon atoms, and the lower-alkenoyl moiety thereof contains from three to five carbon atoms, and in either case can be straight or branched.

When R or R is cycloalkyl-lower-alkyl or when R, is cycloalkanecarbonyl, cycloalkyl-lower-alkanoyl, carboxycycloalkylcarbonyl, hydroxymethyl-cycloalkylrnethyl, or N-cycloalkylcarbamyl, the cycloalkyl moiety thereof contains from three to seven ring carbon atoms, and the lower-alkyl or loWer-alkanoyl moieties thereof contain from one to five carbon atoms and can be straight or branched. Thus the cycloalkyl-lower-alkyl radical includes such radicals as cyclopropylmethyl, cyclopropylcarbonyl, cyclobutylmethyl, cyclobutylcarbonyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylcarbonyl, 2-carboxycyclohexanecarbonyl, 2-(cyclohexyl)ethyl, B-cyclohexylpropionyl, S-(cyclohexyDpentyl, cycloheptylmethyl, and the like.

In the above general Formula I, R stands, inter alia, for hydrogen or from one to five loWer-alkyl radicals. When R is one or more lower-alkyl radicals, each loweralkyl radical can contain from one to about four carbon atoms, can be straight or branched and can occupy any of the five available positions on the piperidine ring, and when R is more than one lower-alkyl radical, said radicals can be the same or different and can occupy the same or different positions on the piperidine ring. Thus R stands, inter alia, for methyl, ethyl, isopropyl, n-butyl, isobutyl, and the like.

When R represents lower-alkyl, carboXy-lower-alkanoyl, cyano-lower-alkyl, amidoximino-lower-alkyl, or lower-alkyl-keto-loWer-alkanoyl, the lower-alkanoyl or lower-alkyl moieties thereof contain from one to eight carbon atoms and can be straight or branched. Thus R also represents, inter alia, methyl, ethyl, propyl, isobutyl, heptyl, succinoyl, glutaryl, 2-cyan0ethyl, 3-cyanpropyl, 3- amidoximinopropyl, 4 amidoximinobutyl, 2 ketopropyl, 3-ketobutyl, and the like.

In the above general Formula I, Y is lower-alkylene containing from two to eight carbon atoms and interposing at least two carbon atoms between the amino nitrogen atom of the (l-piperidyl)-lower-a1kylamino group and the ring nitrogen atom of the piperidine nucleus. The lower- 4 alkylene group can be straight or branched and thus stands, inter alia, for 1,2-ethylene [-CH CH 1,3- propylene [(CH 1,2-(2-methylethylene) 1,4-butylene [(CH 1,5-pentylene [(CH 1,6-hexylene [(CH 1,7-heptylene [(CH 1,8-octylene [--(CH and the like.

The monoand bis-[(l-piperidyl)-lower-alkyl]amines of Formula I where R; is H are prepared by reducing, with hydrogen in the presence of a catalyst, a 1-(cyano-loweralkyl)-piperidine having the formula where R and R have the meanings given above; and Y is lower-alkylene containing from one to seven carbon atoms and interposing at least one carbon atom between the ring nitrogen atom of the piperidine nucleus and the cyano group. As will be described hereinafter, the compounds of Formula III have further utility other than as intermediates, and When not used as intermediates, the group R in compounds of Formula III, represents in addition certain carbo-lower-alkoxy groups of a nature to be more fully described hereinafter. These latter compounds are also considered to be within the purview of the invention.

The reduction of the compounds of Formula III is carried out in an organic solvent inert under the conditions of the reaction, for example, methanol, ethanol, or isopropanol, at a temperature in the range from about 20 C. to about 70 C. and at hydrogen pressures in the range from about 40 pounds p.s.i. to about 1,000 pounds p.s.i. When the reduction is carried out in a neutral medium, the bis-[(l-piperidyl)-loWer-alkyl]amines of Formula I (n is 2, R is H) are the predominant products although the mono-[(1piperidyl)-lower-alkyl]amines (n is 1, R is H) are also produced in minor amounts. On the other hand, it the solvent used is first saturated with anhydrous ammonia, so that the reaction medium is strongly ammoniacal, the predominant products are the mono-[(l piperidyl)-lower-alkyl]amines, although the bis-[(l-piperidyl)-loWer-alkyl]amines are also produced in minor amounts. Suitable catalysts are platinum oxide, palladium-on-charcoal, and rhodium-on-alumina. A preferred catalyst is rhodium-on-alumina.

The 1-(cyano-lower-alkyl)piperidines of Formula III where Y is lower-alkylene interposing two carbon atoms between the cyano group and the ring nitrogen atom of the piperidine nucleus are prepared by reacting an acrylonitrile with a piperidine in the presence of a basic catalyst. The reaction is represented by the equation:

where R and R have the meanings given above and each of R and R stands for hydrogen or the methyl radical, or one of R and R is hydrogen while the other is the ethyl radical. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, for example, water, benzene, dioxane, pyridine, or acetonitrile. A preferred solvent is water. Suitable basic catalysts are tri-lower-alkylamines, for example, triethylamine, or basic tertiary heterocyclic amines, for example pyridine, or quaternary ammonium hydroxides, for example Triton B (benzyl trimethylammonium hydroxide). A preferred basic catalyst is triethylamine.

The compounds of Formula III Where Y is loweralkylene interposing from one to seven carbon atoms between the cyano group and the ring nitrogen atom of the piperidine nucleus are prepared by reacting a cyano-loweralkyl halide with an appropriately substitutedpiperidine in the presence of an acid-acceptor. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, for example, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, and the like. The purpose of the acid-acceptor is to take up the hydrogen halide split out during the course of the reaction and is a basic substance which forms water-soluble by-products easily separable from the main product of the reaction and includes such substances as alkali metal salts of weak acids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, and the like. The acid-acceptor can also be in the form of an excess quantity of the substitutedpiperidine.

The compounds of Formula I where R is benzoyl, phenyl-lower-alkanoyl, lower-alkanoyl, halo-lower-alkanoyl, cycloalkane-carbonyl, cycloalkyl-lower-alkanoyl, carboxy-cycloalkylcarbonyl, phenoxy-lower-alkanoyl, phenyllower-alkenoyl, carboxy-lower-alkanoyl, phenylsulfonyl, or a divalent residue of a dibasic carboxylic acid are prepared by reaction of the compounds of Formula I where R, is hydrogen with the corresponding acid halide. The reaction is preferably conducted in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, xylene, dioxane, and the like, and at a temperature in the range from 50 C. to 150 C. The reaction can if desired be carried out in the presence of an acid-acceptor to take up the hydrogen halide split out during the course of the reaction. Suitable acid-acceptors are alkali metal hydroxides, for example, sodium or potassium hydroxide, alkali metal carbonates or bicarbonates, for example, sodium or potassium carbonate or sodium or potassium bicarbonate, or an excess of the amine starting material.

Another method for preparing the compounds of Formula I where R is benzoyl, lower-alkanoyl, cycloalkane-carbonyl, carboxy-cycloalkylcarbonyl, or a divalent residue or a dibasic carboxylic acid, and which can also be used to prepare the compounds of Formula I where R; is loWer-alkyl-keto-lower-alkanoyl or carboxy-lower-alkanoyl comprises reacting the secondary amines of Formula I where R, is hydrogen with the corresponding acid anhydride. The reaction is preferably conducted in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, xylene, dioxane, and the like, and at a temperature in the range from 20 C. to 150 C. The reaction is preferably carried out in the presence of a basic catalyst for example, pyridine or triethylamine.

The compounds of Formula I where R is ,B-phenylpropionyl are advantageously prepared from the corresponding N-cinnamoyl compounds (R is cinnamoyl or substituted cinnamoyl), (which in turn are prepared by reaction of the secondary amine with a cinnamoyl halide as described above) by catalytic reduction of the cinnamamide with hydrogen. The compounds where R, is fl-phenylpropionyl are produced when reduction is stopped after the uptake of one mole of hydrogen, and the compounds where R, is p-cyclohexylpropionyl are produced if the reduction is allowed to proceed to the uptake of four moles of hydrogen. The reaction is conducted in an organic solvent inert under the conditions of the reaction, for example, methanol, ethanol, propanol, and the like, and at hydrogen pressures in the range from 40 to pounds p.s.i. Suitable catalysts are palladium-oncharcoal, platinum oxide and palladium oxide.

The compounds of Formula I where R is benzyl, phenyllower-alkyl, loWer-alkyl, cycloalkyl-lower-alkyl, hydroxymethylcycloalkylmethyl, phenoxy-lower-alkyl, hydroxy-loweralkyl, or lower-alkylene are prepared by reducing, with an alkali metal aluminum hydride, the corresponding amides, i.e. the compounds where R, is, respectively, benzoyl, phenyl-lower-alkanoyl, lower-alkanoyl, cycloalkyl lower-alkanoyl, carboxy-cycloalkylcarbonyl, phenoxy-lower-alkanoyl, carboxy-loWer-alkanoyl, or a divalent residue of a dibasic carboxylic acid. The reaction is carried out at a temperature in the range from 0 C. to about 65 C. in an organic solvent inert under the conditions of the reaction, for example, dioxane, tetrahydrofuran, diethyl ether, dibutyl ether, and the like. A preferred reducing agent is lithium aluminum hydride.

An alternative procedure for preparing the compounds of Formula I where R, is methyl comprises reductive alkylation of the amines where R, is hydrogen with formaldehyde and formic acid using the Eschweiler-Clarke modification of the Leuckart reaction. The reaction is preferably conducted in an excess of formic acid as the solvent at the reflux temperature thereof.

Another method of preparing the compounds of Formula I where R, is benzyl comprises reacting the secondary amines of Formula I where R, is hydrogen with a benzyl halide. The reaction is preferably conducted in an organic solvent inert under the conditions of the reaction, for example, benzene, ethanol, methanol, and the like, at a temperature in the range from 50 C. to C. The reaction is preferably carried out in the presence of an acid-acceptor to take up the hydrogen halide split out during the course of the reaction. Suitable acid-acceptors are alkali metal carbonates or bicarbonates, for example, so-

dium or potassium carbonate or sodium or potassium bicarbonate, or alkali metal hydroxides, for example, sodium or potassium hydroxide.

An alternative method for preparing the compounds of Formula I where R is Z-hydroxyethyl comprises reacting the amines of Formula I where R, is hydrogen with ethylene oxide. The reaction is preferably conducted in an autoclave at temperatures in the range from 100 to 250 C. and in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, lower-alkanols, and the like.

The compounds of Formula I where R is N-loweralkylcar-bamyl, N-lower-alkylthiocanbamyl, N-cycloalkylcarbamyl, N-phenylcarbamyl, N-phenylthiocarbamyl, carbamyl, thiocarbamyl, or dicarbamylbiphenyl comprises reacting the compounds of Formula I where R; is hydrogent with a ilower-alkylisocyanate, lower-alkylisothiocyanate, cycloalkylisocyanate, phenylisocyanate, phenylisothiocyanate, isocyanic acid, isothiocyanic acid, or biphenyldiisocyanate, respectively. The reaction is preferably conducted in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, acetone, lower-alkanols, and the like. Reaction generally takes place at room temperature, although heating at the boiling point of the solvent may sometimes be desirable to effect react-ion.

The compounds of Formula I where R, is cyano-loweralkyl are prepared by reacting the compounds of Formula I where R is hydrogen with a cyano-lower-alkyl halide in the presence of an acid-acceptor and at temperatures in the range from 50 to 150 C. The reaction is preferably carried out in an organic solvent inert under the conditions of the reaction, for example, methanol, ethanol, benzene, toluene, and the like. The purpose of the acid-accep tor is to take up the hydrogen halide which is split out during the course of the reaction and can be any basic substance which forms water-soluble salts easily separable from the reaction mixture. Suitable acid-acceptors are 7 .alkali metal hydroxides, for example, sodium or potassium hydroxide, alkali metal carbonates or bicarbonates, for example, sodium or potassium carbonate or sodium or potassium bicarbonate, and the like.

Alternatively the compounds of Formula I where R, is 2-cyanoethyl can be prepared by reacting the compounds of Formula I where K; is hydrogen with acrylonitrile. The reaction is carried out in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, methanol, acetone, and the like. It is preferred to conduct the reaction in an excess of the acrylonitrile at the boiling point thereof.

The compounds of Formula I where R; is amidoximino-loweraalkyl are prepared from the compounds where R, is the corresponding cyano-lower-alkyl group by reacting the latter with hydroxylamine in the presence of a basic catalyst, for example, sodium carbonate, in an organic solvent inert under the conditions of the reaction, for example, methanol, ethanol, isopropanol, and the like, and at a temperature in the range from 50 tol C. A preferred solvent is ethanol.

The compounds of Formula I where R, is amidino are prepared by reacting the compounds of Formula I where R; is hydrogen with a 2-loweralkyl-2-thio-pseudourea. The reaction is carried out at a temperature in the range from 20 to 100 C. and in an organic solvent inert under the conditions of the reaction, for example, methanol, ethanol, isopropanol, acetone, and the like.

The compounds of Formula where R is N, N-di-lowerialkylcarbamyl, N,N-di-lower-alkylthiocarbamyl, piperidinocarbonyl, py-rrolidinocarbonyl, piperidinothiocarbonyl, or pyrrolidinothiocarbonyl are prepared by reacting the compounds of Formula I where R, is hydrogen with an N,N-di-lower-alkylcarbamyl chloride, N,N-di-loweralkythiocarbamyl chloride, piperidinocarbonyl chloride, pyrrolidinocarbonyl chloride, piperidinothiocarbonyl chloride, or pyrrolidinothiocarbonyl chloride, respectively. The reaction is preferably carried out in the presence of an acid-acceptor and in an organic solvent inert under the conditions of the reaction, for example, benzene, toluene, acetone, and the like. The purpose of the acid-acceptor is to take up the hydrogen halide which is split out during the course of the reaction and can be any basic substance which forms water-soluble salts easily separable from the reaction mixture. Suitable acid-acceptors are for ex ample, alkali metal carbonates or bicarbonates such as sodium or potassium carbonate or sodium or potassium bicarbonate.

The novel compounds of the instant invention are the compounds of Formula I and their acid-addition salts. The compounds of Formula I, in free base form, are converted to the acid-addition salt form by interaction of the base with an acid. In like manner, the free bases can be regenerated from the acid-addition salt form in the conventional manner, that is, by treating the salts with strong aqueous bases, for example, alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates. T-he bases thus regenerated can then be interacted with the same or a different acid to give back the same or a different acid-addition salt. Thus the novel bases and all their acid-addition salts are readily interconvertible.

It will thus be appreciated that Formula I not only represents the structural configuration of the bases of the invention but is also representative of the structural entity which is common to all of our compounds of Formula I, whether in the form of the free bases or in the form of the acid-addition salts of the bases. We have found that by virtue of this common structural entity, the bases and their acid-addition salts have inherent pharmacodynamic and chemotherapeutic activity of a type to be more fully described hereinbelow. This inherent pharmacodynamic and chemotherapeutic activity can be enjoyed in useful form for pharmaceutical purposes by employing the free bases themselves or the acid-addition salts formed from pharmaceutically-acceptable acids, that is acids whose anions are innocuous to the animal organism in effective doses of the salts so that beneficial properties inherent in the common structural entity represented by the free bases are not vitiated by side-effects ascriba'ble to the anions.

In utilizing this pharmacodynamic activity of the salts of the invention, we prefer of course to use pharmaceutically-acceptable salts. Although water-insolubility, high toxicity, or lack of crystalline character may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the Waterinsoluble or toxic salts can be converted to the correspond ing pharmaceutically-acceptable bases by decomposition of the salt with aqueous base as explained above, or alternatively, they can be converted to any desired pharmaceutically-acceptable acid-addition salt by double decomposition reactions involving the anion, for example, by ion-exchange procedures.

Moreover, apart from their usefulness in pharmaceutical applications, our salts are useful as characterizing or identifying derivatives of the free bases or in isolation or purification procedures. Like all of the acid-addition salts, such characterizing or purification salt derivatives can, if desired, be used to regenerate the pharmaceutically-acceptable free bases by reaction of the salts with aqueous base, or alternatively can be converted to a pharmaceutically-acceptable acid-addition salt by, for example, ionexchange procedures.

It will be appreciated from the foregoing that all of the acid-addition salts of our new bases are useful and valuable compounds, regardless of considerations of solubility, toxicity, physical form, and the like, and are accordingly within the purview of the instant invention.

The novel feature of the compounds of the invention, then, resides in the concept of the bases and cationic forms of the new monoand bis-[(l-piperidyl)-lower-alkyl] amines and not in any particular acid moiety or acid anion associated with the salt forms of the compounds; rather, the acid moieties or anions which can be associated in the salt forms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with bases. In fact, in aqueous solutions, the base form or water-soluble acidaddition salt form of the compounds of the invention both possess a common protonated cation or ammonium ion.

Thus the acid-addition salts discussed above and claimed herein are prepared from any organic acid, inorganic acid (including organic acids having an inorganic group therein), or organo-metallic acid as exemplified by organic monoand poly-carboxylic acids; such as found, for example, in Beilsteins Organische Chemie, 4th ed., volumes III, IV, IX, X, XIV, XVII, XIX, XXI, XXII, XXV; organic monoand poly-sulfonic and -sulfinic acids; such as found, for example, in Beilstein volumes VI, XI, XVI, and XXII; organic phosphonic and phosphinic acids; such as found, for example, in Beilstein volumes XI and XVI; organic acids of arsenic and antimony; such as found, for example, in Beilstein volume XVI; organic heterocyclic carboxylic; sulfonic, and sulfinic acids such as found, for example, in Beilstein volumes XVIII, XXII, and XXV; acidic ion-exchange resins, for example, Amberlite XE-66 resin; and inorganic acids of any acidforming element or combination of elements, such as found in Mellor, Comprehensive Treatise on Inorganic and Theoretical Chemistry, Longmans, Green and Co., New York, N.Y., volumes I-XVI. In addition, other saltforrning compounds which are acidic in their chemical properties, but which are not generally considered as acids in the same sense as carboxylic or sulfonic acids. are also considered to be among the numerous acids which can be used to prepare acid-addition salts of the compounds of the invention. Thus there is also comprehended acidic phenolic compounds, such as found, for example, in volume VI of Beilstein, acidic compounds having activated or acidic hydrogen atoms, as for example, picrolonic acid, or barbituric acid derivatives having an acidic proton, such as found, for example, in Cox et al. Medicinal Chemistry, vol. IV, John Wiley and Sons, Inc., New York, NY. (1959). Also comprehended as salt forming agents are so-called Lewis acids which lack a pair of electrons in the outer electron shell and react with basic compounds having an unshared pair of electrons to form salts, for example, boron trifiuoride.

Thus appropriate acid-addition salts are those derived from such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic caid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, Z-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, paminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, Amberlite XE-66 resin, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Pharmacological evaluation of the compounds of Formula I have shown that they possess pharmacodynamic and chemotherapeutic properties, in particular, anti-inflammatory, coronary dilator, hypotensive, anti-fungal, anthelmintic, and psychomotor depressant activities thus indicating their usefulness as anti-inflammatory, antifungal and blood pressure lowering agents, coronary dilators, anthelmintics, and tranquilizers.

The structures of the compounds of the invention are established by their mode of synthesis and corroborated by the correspondence between calculated values for the elements and values found by chemical analysis.

The following examples will further illustrate the invention without the latter being limited thereto.

EXAMPLE 1 1-(2-cyan0ethyl)-4-carbamylpiperidine [111: R is R3 is Y IS To a solution of 18.82 g. (0.10 mole) of 4-carbamylpiperidine acetate and 13.11 g. (0.11 mole) of triethylamine in 125 ml. of water in a 250 ml. three-necked flask equipped with a stirrer, a thermometer, and a dropping funnel was added dropwise, over a period of one hours, 5.58 g. (0.11 mole) of acrylonitrile while maintaining the temperature between 14 and 20 C. The mixture was allowed to warm to room temperature, stirred for an additional hour and allowed to stand overnight at room temperature. The mixture was then treated with 40 g. of solid potassium carbonate and the mixture extracted with chloroform. The chloroform extracts were dried over Drierite filtered, and the solvent removed in vacuo leaving a white residual solid. The latter was recrystallized from ethyl acetate giving 12.4 g. of 1-(2-cyanoethyl)-4 carbamylpiperidine, M.P. 151.0152.6 C. (corr.).

1-(2-cyanoethyl) 4 carbamylpiperidine reacts with formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1 naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crontonic acid, acetylene dicarboxylic acid, sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, Z-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid, benzene-sulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphonic acid, phenylphosphinic acid, Amberlite XE-66 resin, hydrofluoric acid, hydrochloric acid, hydrochloric acid, hydrobrornic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like, to give, respectively, the formate, acetate, isobutyrate, alpha-mercaptopropionate, malate (or acid malate), fumarate (or acid fumarate), succinate, (or acid succinate), succinamate, tartrate (or bitartrate), citrate (or acid citrate), lactate, benzoate, 4-methoxybenzoate, phthalate (or acid phthalate), anthranilate, 1- naphthalenecarboxylate, cinnamate, cyclohexanecarboxylate, mandelate, tropa-te, orotonate, acetylene dricarboxylate, sorbate (or acid sorbate), Z-furancarboxylate, cholate, pyrenecarboxylate, 2-pyridinecarboxylate, 3-indoleacetate, quinate, sulfarnate, methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, benzenesulfinate, butylarsonate, diethylphosphinate, p-aminophenylarsinate, phenylstibnate, phenylphosphinite, methylphosphonate, phenylphosphinate, Amberlite XE-66 resin salt, hydrofluoride, hydrochloride, hydrobromide, hydriodide, perchlorate, nitrate, sulfate (or bisulfate), phosphate (or acid phosphate), hydrocyanide, phosphotungstate, molybdate, phosphomolyhdate, pyrophosphate, arsenate, picarate, picrolonate, barbiturate, and boron trifiuoride salts.

1-(2-cyanoethyl)-4-carbamylpiperidine can be reacted with hydriodic acid to form 1-(2-cyanoethyl)-4-carbamylpiperidine hydriodide, useful as a characterizing intermediate.

1-(2-cyanoethyl)-4-carbamylpiperidine, in the form of its hydriodide salt, can be converted to the hydrochloride salt by passing an aqueous solution of the former over an ion-exchange resin saturated with chloride ions, for example, Rohm and Haas Amberlite IRA-400 resin.

EXAMPLE 2 1-cyan0methyZ-4-cycl0hexylmethylpiperidine [111: R is 4CH2C5H11; R3 IS H; Y IS A solution of 36. 2 g. (0.20 mole) of 4-cyclohexylmethylpiperidine and 7.55 g. (0.10 mole) of chloroacetonitrile in ml. of benzene was heated under reflux for three hours after the initial reaction had subsided. The solid 4-cyclohexylmethylpiperidine hydrochloride which had separated was filtered off, and the filtrate taken to dryness. Recrystallization of the residue once from hexane and once from methanol/water afforded 15.9 g. of 1- cyanomethyl-4-cyclohexylmethylpiperidine, M.P. 78.5- 79.8 C. (corr.).

EXAMPLES 321 The compounds of Formula III listed below in Table 1, where Y CH CH were prepared from acrylonitrile and an appropriate substituted-piperidine according to the procedure described above in Example 1, and the compounds, where Y is (CH (CH (CH or (CH were prepared according to the procedure described in Example 2. R in each case is hydrogen. All melting points, given for the free base form, are corrected unless noted otherwise.

TABLE 1 R, Y M.P. C.) Cryst. irm

4-CONHCH3 CH2C,T{2 l] 6.4117.2 Ethyl acetate. 4-CONHC2II5 01 12011: 1l0.6111.8 Benzene/hexane. 4-CON(CH:4)1 CHzCHz 65.0 668 Ethyl acetate/hexane. 4-CON(CzI-I5)g CHgCHg B.P.,151159/0.07 13 IIIHL- i-GHzOH OHZCHQ 13.1 l02.0l04.1/0.0650.071 111111.;

/L -l.493[). 4-(OI-IZ)3OH CI'IZCHQ 44.245,4 2-COOO2H CI-I CH B.P., 64.166.5/0.0290.031 111111.;

'rm =1.4675. 3-OOOCH3 CH2CHZ 13.2 73 6872/0.023 mm.; nD

1. 5. 4-COOCI-I3 CHzCHz 42443.4 b 4COOCH CH(CH3) CHZCHZ 205207/l6mm.;m =l.4660

4CH CaH CHzCI-Iz 13.13., 131.5-135/0.08 111.111.; 7m

1.5289. 4-OHzC5H11 01110112 3.11, 102.0'112/012 mm.; M3

1. 9. 4-CHzOsH11 (31120113 B.P., 102.01l2/0.12 111111.; H13

1.4889. t n CHzCH-z B.P.. 106.511l.5/0.07-0.09 111111.;

nD =l.4948. 'i-GHzCeHu (CH 45.655.2 I'Iexane. 4-CH CnHu (CH2)4 B.P., 113114/0.001 111111.; nD

. 6 Z-CH CGH (0111). 13.11% 1%4-130/0D25 IHIIL; 771D:

1. 98. i-GHcCuHu (CH2)5 40.0-42.8 D0. 4-CH C H11 (CHm B.1P.,44l49l52/0.059 mrn.; nn

B Hydrochloride salt, recrystallized from ethanol/ether has MI. 185188 C. (uncom). b B.P. 123-124" C./0.38 mm.

Hydrochloride salt, recrystallized from acetone, gave Ml. 204.8-206.0 C. (corn).

d Hydrochloride salt, recrystallized from acetone, gave M.P. 150.0152.4 C. (corn).

@ Hydrochloride salt, recrystallized from acetone, gave Ml 187.4189.9 C. (c0rr.).

EXAMPLE 22 1-cyan0methyl-2,6-dimethyl-4-hydroxypiperidine [111: R is 4-HO; R is 2,6-di-CH Y is CH By reacting 2,6-dimethyl-4-hydroxypiperidine with an 40 EXAMPLE 31 3-(4-carbamyl-1-piperidyl)propylamine [I1 R is 4-CONH R and R are H; Y is (CH n is 1] To a solution of 34.75 g. (0.19 mole) of 1-(2-cyano equimolar amount of u-bromoacetonitrile in the presence of an acid-acceptor, for example, sodium carbonate, in an organic solvent inert under the conditions of the reaction, for example, acetonitrile, and isolating the prodnot from an alkaline medium, there can be obtained 1-cyanornethyl-2,6-dimethyl-4-hydroxypiperidine.

EXAMPLE 23 1 (4 cyanobutyl) 4 hydr0xy-2,2,4,6,6-pcrztamethylpiperidine [111: R is 4-HO; R is 2,2,4,6,6-penta-CH is 2)4] By reacting {-bromovaleronitrile with 4-hydroxy-2,2,4, 6,G-pentamethylpiperidine according to the manipulative procedure described above in Example 22, there can be obtained 1 (4 cyanobutyl) 4 hydroxy-2,2,4,6,6-pentamethylpiperidine.

EXAMPLES 24-30 Ex. R2 Ra 4-HO 2,2-di-C1I3-6-(CII3)QCHCHZ CHQGOH 4-NHCHO 4-C O N C411 ethyl)-4-carbarnylpiperidine in 450 ml. of ethanol saturated with anhydrous ammonia was added 4.2 g. of a 5% rhodium-on-alumina catalyst. The mixture was reduced with hydrogen under an initial pressure of 210 pounds p.s.i. at a temperature of 25 C. Reduction was complete in three hours. The catalyst was removed by filtration, washed with ethanol, the filtrate concentrated to dryness in vacuo and the white crystalline residue extracted with acetone, filtered, and the filtrate taken to dryness yield- 5 ing 25.4 g. of a white powder which was recrystallized twice from a benzenehexane mixture giving 22.0 g. of 3-(4-carbamyl-1-piperidyl)propylamine, M.P. 85-88 C. (uncorr.).

3 (4 carbamyl 1 piperidyl)propylamine reacts with formic acid, acetic acid, isobutyric acid, alpha mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cy-

0 clohexane carboxylic acid, mandelic acid, tropic acid,

crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2- furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2 pyridinecarboxylic acid, 3 indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid,

benzenesulfonic acid, p toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, paminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, rnethylphosphonic acid, phenylphosphinic acid, Amberlite XE-66 resin, hydrofluoric acid, hydro- 70 chloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like, to give, respectively, the formate,

Example 1 4 EXAMPLES 48-58 By following the manipulative procedure described above in Example 31, substituting for the 1-(2-cyano ethyl)4-carbamyl-piperidine used therein, a molar equivalent amount of the 1-(cyano-lower-alkyl)-substitutedpiperidines described above in Examples 6, 7, and 22-30, there can be obtained the respective (Substituted 1 piperidyl)-lower-alkylamines of Formula I (R; is H; n is sulfamate, methanesulfonate, 1) listed below in Table 4.

TABLE 4 2,6-di-CI-Ia isethionate, benzenesulfonate, p toluenesulfonate, benzenesulfinate, butylarsonate, diethylphosphinate, 6-arninophenylarsinate, phenylstibnate, phenylphosphinite, methylphosphonate, phenylphosphinate, Amberlite XE-66 resin salt, hydrofluoride, hydrochloride, hydrobromide, hydriodide, perchlorate, nitrate, sulfate, (or bisulfate), phosphate (or acid phosphate), hydrocyanide, phosphotungstate, molybdate, phosphomolybdate, pyrophosphate, arsenate, picrate, picrolonate, barbiturate, and boron trifluoride salts.

3 (4 carbamyl 1 piperidyl)propylamine can be reacted with hydriodic acid to form 3 (4 carbamyl 1- piperidyl)propylamine hydriodide, useful as a characterising intermediate.

3 (4 carbamyl 1 piperidyl)propylamine, in the form of its hydriodide salt, can be converted to the hydrochloride salt by passing an aqueous solution of the former over an ion-exchange resin saturated with chloride ions,

for example, Rohm & Haas Arn-berlite IRA-400 resin.

EXAMPLES 32-47 The following rnono[(1-piperidyl)lower-alkyl] amines of Formula I [n is 1; R and R are H] listed below in Table 3 were prepared according to the procedure de- EXAMPLE 59 N,N bis {3 [4 (N- methylcarbzzmyl) J piperz'dyl] pv-opyl}amine [1: R is 4-CONHCH R is H; R, is H; Y is (CI-I 0 n is 21] 1 (2 cyanoethyl) 4 (N methyl-carbamy1)piperidine (39 g., 0.20 mole) was dissolved in 500 ml. of ethanol saturated with anhydrous ammonia and reduced over 4 g. of a rhodium-on-alumina catalyst under 208 pounds p.s.i. of hydrogen. When reduction was completed, the catalyst was removed by filtration and the filtrate taken to dryness leaving a waxy white solid. The latter was extracted with five 300 ml. portions of boiling ether and the extracts, which contained the mono-amine, were set aside for further work. The ether-insoluble material was boiled with 200 ml. of acetone and dried giving 8.6 g. of material of M.P. -195 C. (uncorr.). The latter was recrystallized from an ethanol/acetone mixture giving 6.8 g. of N,N-bis-{3-[4-(N-methylcarbamyl)-1-piperidyl]propyl}amine, M.P. 203.0203.8 C. (corn).

Analysis.-Calcd. for C H N O 11.01. Found: N 18.29; N 11.02.

TABLE 3 Example R; Y Base or M.P. C.) Cryst. from Salt 4-CONHCH3 (CH2)3 2HCl 239. 6-240. 6 Ethanol/ether. 4-CONCHZH CH2)3 2HC1 2450-2402 D0. 4-CON(CH3)2 (011;)3 Base 4-CON(C2H (CHm Base 0 4-CH2CGH5 (C1193 2HC1 191.6193.4 Do. 443112061111 (CI-I'm 2HC1 280. 2-2824 Do. 4-1-10 (II-I93 Base 0 4-HO(CH2)3 (OHm Base 163.8165.2 Isoproponal. 4-(CHa)2CI-I (CHm 21101 215. 2-217.8 Do.

3-CH3CONH (CI-12):; Base 4-CH2C6H11 (CHM 2HC1 259. 8-262. 8 Ethanol/acetone. ZCI'IQCBHH (01193 21101 2000-2068 Isopropanol. 4-CHzCoHn (CHM 21101 262. 8-266. 0 Do. 4CH2C6H11 CH2)5 ZHCI 250. 6-257.2 D0.

4-CHzCeH11 (C1396 ZHCI 231. (5-236. 2 Ethanol. 4-CH2C6I-In (CH2)1 21101 247. 0-249. 6 Acetone.

i collected and recrystallized from an ethanol/ether mixture giving 5.5 g. of 3-[4-(N-methylcarbamyl)-1-piperidyl]propy1amine dihydrochloride, M.P. 238240 C. (uncorr.).

N,N bis {3 [4 (N' methylca-rbamyl) 1- piperidyl]propyl}amine reacts with formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexane-carboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphonic acid, phenylphosphinic acid, Amberlite XE-66 resin, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifiuoride, and the like, to give, respectively, the formate, acetate, isobutyrate, alpha-mercaptopropionate, malate (or acid malate), fumarate (or acid fumarate), succinate (or acid sucbutyl-arsonate, diethylphosp-hinate, p-aminophenylarsinate, phenylstibnate, phenylphosphinite, methylphosphonate, phenylphosphinate, Amberlite XE-66 resin salt, hydrcfiuoride, hydrochloride, hydrobromide, hydriodide, perchlorate, nitrate, sulfate (or bisulfate), phosphate (or acid phosphate), hydrocyanide, phosphotungstate, molybdate, phosphomolybdate, pyrophosphate, arsenate, picrate, picrolonate, barbiturate, and boron trifluoride salts.

N,N bis {3 [4 (N' methylcarbamyl) 1 piperidyl]propyl}amine can be reacted with hydriodic acid to form N,N, bis {3 [4 (N' methylcarbamyl) 1- piperidyl]propyl}amine hydriodide, useful as a characterizing intermediate.

N,N bis {3 [4 (N'-methylcarbarnyl) 1 piperidyl]propyl}amine, in the form of its hydriodide salt, can be converted to the hydrochloride salt by passing an aqueous solution of the former over an ion-exchange resin saturated with chloride ions, for example, Rohm and Haas Amberlite IRA-400 resin.

EXAMPLES 60-73 The following N,N-bis-[(l-piperidyl)-lower-alkyl]- amines of Formula I [n is 2; R and R are H] listed below in Table 5 Were prepared according to the procedure described above in Example 59 by reduction of an appropriate l-(w-cyano-lower-alkyl)piperidine of Formula III with hydrogen over a rhodium-on-alumina catalyst. All melting points are corrected.

TAB LE 5 Example Ra Y Bgseltor M.P. C.) Crystd. from- 6O 4-CONHCH (GI-Iz)a Base 191. 2-192. 8

4-CON (CH3): (CH2); Base 87. 8-88. 6 Hexane. 4-CHgOuH5 (CH2)3 3HC1 26G. 6-268. 0 Ether. 40112061111 (CHm 31101 300 Isopropanol/ethcr. 4"(OH3)2CH (CHz)3 Base 0) 4H0 (CHm Base 4-HO (CH2): (CHm 31101 191. 2-199. 4 Isopropanol. 4-CHzCsI'Iu (0112):; 3HCl 294. 4-298. 2 Ethanol. 4-OH CgHn (CH2); Base 37. 2-43. 0 Acetone. Z-CHZCflHll (CH-2):; 3HC1 179. 2-192. 4 Do. 4'OH CGH (011;); Base 50. 2-51. 0 Hexane. 4CII2C6H11 (CHM Base 57. 2-58. 5 Acetone. 4-CHzCaH11 (CHm Base 52. 4-54. 6 Do. 4-CH OBH 1 (CH2)1 Base 63. 6-64. 4 D0.

B B1. 125.5131.0 C./0.0015 mm.; nD =1.4832. Trihydrochloride,

recrystallized from isop ropanol, gave M.P. 291.2293.4 0. (corn).

b 13.1. 186-193 G./0.0020.0024 mm; n =1.5197.

EXAMPLES 74-83 By following the manipulative procedure described above in Example 59, substituting for the 1-(2-cyanoethyl)-4-(N methylcarbamyl)piperidine used therein, a molar equivalent amount of the l-(cyano-lower-alkyD- substituted-piperidines described above in Example 6, and 2230, there can be obtained the respective N,N-bis-[(substituted-l-piperidyl)-loWer-a1kyl] amines of Formula I (R is H; n is 2) listed below in Table 6.

TABLE 6 2,6-diCH3. 2,2,4,6,6-pcnta-CHa. 2 2-di-CH -6-(CH3 OHCH 17 EXAMPLE 84 The following N-(R )-N,N-bis-[(4-cyclohexylmethyl-1- piperidyl) lower alkyl] amines of Formula I [R is 4-CH C H R is H; n is 2] listed below in Table 7 were prepared using the procedure described above in Example 84 by reaction of an appropriate acid chloride with an appropriate N,N-bis-[(4-cyclohexylmethyl 1 piperidyl)- lower-alkyl] amine. All melting points are corrected.

18 EXAMPLE 123 N-acetyl-N,N-bis-[3-(4-cyclohexylmethyl 1 piperidyl) propyl]am ine dihydrochloride [I1 R is 4-CH C H R is H; R; is CH CO; Y is (CH n is 2] A solution of 13.8 g. (0.03 mole) of N,N-bis-[3-(4- cyclohexylrnethyl-l piperidyDpropylJamine, 4 g. (0.04 mole) of acetic anhydride, and m1. of pyridine was allowed to stand overnight at room temperature and then warmed one hour on a steambath. The mixture was taken to dryness in vacuo; the residual oil was dissolved in ml. of benzene and the solution washed once with dilute potassium carbonate, several times with water, and taken to dryness. The residual oil was distilled in vacuo, the fraction boiling at 203-210 C./ 0.002 mm.

being collected as product.

A small amount of the oil, converted to the hydrochloride salt and recrystallized from absolute ethanol, gave N-acetyl-N,N-bis-[3-(4-cyclohexylmethyl 1 piperidyl) propyl1amine dihydrochloride, M.P. 277.2279.0 C. (corn).

EXAMPLES 123-134 The following N-(R N,N bis [(4 cyclohexylmethyl-l-piperidyl)-lower alkyl] amines of Formula I [R is 4-CH C H R is H; n is 2] listed below in Table 8 were prepared according to the procedure described above in Example 123 by reacting an appropriate acid anhydride with an appropriate N,N-bis-[ (4 cyclohexylmethyl 1- piperidyD-ldwer-alkyl] amine. All melting points are corrected.

TAB LE7 Example Y R; B gszitor M.P. 0.) Cryst. from- CGHSCO Base 41. 2-42. 6 Acetone. Z-OICGHACO 21101 241. 2-243. 0 Isopropanol/acctone. 4-010511400 Base 54. 6-56. 0 cetone. 3,4-0120511300 2H 01 179. 4-182. 8 Do. 4-0H3O 0611400 2H01 245. 2-246. 0 Ethanol/acetone. 4-CH3O CeH4CO 2HC1 202. 4-206. 2 D0. 3-0 F3CQH4C 0 2H0l 231. 0-231. 8 Isopropanol. 40 1 30611400 21101 195. 4-198. 0 Acetone/ether. (0H3) 201100 21101 192. 6-196. 0 Ethanol/acetone. 0H3 (0H2)a00 185. 0-187. 4 Methanol/acetone. CH3 (CH2) 300 21101 181. 0-185. 0 Acetone. (0119 011011 00 21101 180. 4-184. 8 Acetone/ether. 0H3 (0H2)3C0 130. 1-134. 0 Acetone. 0H3 (01121100 2H0] 181. 8-183. 6 Do. CH (CH2) 5C0 2H0l 178. 0-184. 0 Acetone/ethyl acetate. CH3 (CH2) 00 2H 01 191. 6-194 6 Ethanol/ether. CaHsC 2HC1 215. 0-219 4 D0. 0413700 2H 01 195. 6-201 2 Ethanol/acetone/ether. 06111100 21101 224-226 5 Methanol/acetone. 061L100 2H01 187. 0-189. 2 Chloroform/ethyl acetate; 00H5O 011 00 Base 59. 2-63. 4 Acetone. 05H5O CHgOO Base 55. 2-56. 4 Do. 0000 Base 97. 6-992 Do. 00 CHzCHzCO 41101 258. 0-261 0 Methanol/acetone/ether. 0H3(0Hz) 00 2H01 197. 0-199 8 Ethanol/acetone. 00135011 CHCO Base 104.8 106. 2 Acetone. 011115011 CHOO 2H0l 225. 0-227. 0 Ethanol/acetone. 06H50H= 0H0O 21-101 198. 0-201. 0 Ethnnol/acetone/ether. 0H50H= CHCO 2H01 237. 0-240. 0 Methanol/acetone/ether. C(1H5CH=CHCO 2H01 230-232 D0. 4-CH3CeH4SO2 2H0l 188. 0-189. 2 Acetone/ether. 4-NOzCeH4CO 21-101 192-194. 2 Acetone. 3,5-(1i-(NOfl-CnH3CO 21101 255. 0-256. 0 Methanol/acetone. 3-N 0 4-01001 1 00 21101 176. 8-178. 8 Acetone. 3-01-5-HO-0 H30O 21101 186. 4-187. 2 Methanol/ether. 0120H0O 122. 0-125. 4 Acetone/ether. 2-HO 051 1 00 Base 79. 0-82. 6 Hexane. Z-CH3CO2C5H4C 0 109. 0-111. 0 Acetone.

"Bis-cyclohexanesuliamate salt.

TABLE 8 Example Y R4 Base or M.P. C.) Gryst. from- Salt CHaC Base 59.2-61.0 Hexane. CH3CO 2HC1 258. 8-262. 8 Ethanol/ether. CHaGO 2H CLHZO 245. 8-247. 6 D0. (DI-I30 0 121-101 237. 6238. 8 Isopropanol/acetone. CI'IQCHQCO 2HCl 235. 2-237. 4 Ethanol/acetone/ether. CHQCHZC 0 211 O1 226. 0-227. 8 Ethanol/acetone. CHgCHzOO 2H C1 227. 2228. 6 Methanol/acetone. CH3(CH2)2CO 21161 203. 6 206. 4 Ethanol/acetone. OH;(CH) ZOO ZHCl 226. 0-231. 0 Chloroform/acetone. CH3(CH )2CO 21101 201. 8-203. 2 lVlethanol/acetone/ether. CH3(OHz)zC O 2HC1 206. 8-207. 4 Acetone.

EXAMPLE 135 N a (fl-carbo xyprapionyl) -N,N-bis-[3- (4-cycl0hexylmethyl-I-piperidyl)propyl1amine dihydrochloride [1: R is 4- CHZCGHU; R3 is R4 is A mixture of 11.6 g. (0.025 mole) of N,N-bis-[3-(4- cyclohexylmethyl-l-piperidyl)propyl]amine and 2.65 g. (0.026 mole) of succinic anhydride in about 200 ml. of benzene was heated under reflux using a water separator for three hours and then taken to dryness. The residual gum was dissolved in acetone and reprecipitated by addition of hexane, the process being repeated three times, and the remaining gummy material was then dissolved in a small volume of ethanol and acidified by addition of excess ethanolic hydrogen chloride. Precipitation of the resulting salt by addition of ether and recrystallization of the precipitate from acetone/methanol gave 6.2 g. of N- (5 carboxypropionyl) N,N-bis-[3-(4-cyclohexylmethyll-piperidyl)propyl]amine dihydrochloride, M.P. 239.0 (dec., corr.).

EXAMPLE 136 N ([3 carboxypropionyl) -N,N-bis-[6-(4-cyclo hexylmethyl-1 -piperidyl)hexyl]amine dihydrochloride [1: R is 4-CH2C6H11; R3 is R4 is X is (CH n is 2] was prepared from 16.29 g. (0.03 mole) of N,N bis [6-(4-cyclohexylmethyl-l-piperidyl)hexyl] amine and 3.6 g. (0.04 mole) of succinic anhydride in about 250 ml. of benzene using the manipulative procedure described above in Example 135. The product was isolated in the form of the hydrochloride salt and the latter recrystallized from ethanol/ acetone to give 9.4 g. of N- (,B-carboxypropionyl) -N,N-bis- 6- (4-cyclohexylmethyl- 1-piperidyl)hexyl]amine dihydrochloride, M.P. 223.5-

227.5 C. (corr.).

EXAMPLE 137 EXAMPLE 13 8 ..N [N' (2-carbovcyphenyl)carbamvyl]-N,N-bis-[6-(4- cyclohexylmzethyl 1 piperidyl)hexyl]amine [1: R is 4-CH C H R is H; R; is 2-HOOCC H NHCO; Y is (CH n is 2] was prepared from 21.7 g. (0.04 mole) of N,N bis [6 (4 cyclohexylmethyl-l-piperidyl)hexyl] amine and. 7.18 g. (0.044 mole) of isatoic anhydride in about 200 ml. of benzene using the manipulative procedure described above in Example 135 The product was isolated in the form of the free base and the latter recrystallized from methanol to give 9.5 g. of N-[N-(2- carboxyphenyl)carbamoyl] N,N bis-[6-(4-cyclohexylmethyl-l-piperidyl)-hexyl]amine, M.P. 1674-1690 C. (corr.).

EXAMPLE 139 N (2-carboxycyclohexylcarbonyl) N,N bis [6-(4- cyclohexylm'ethyl 1 piperidyl)hexyl] amine dihydrochloride R2 is 4-CH2C5H11; R3 is R4 is z-noocc rr co Y is (CH n is 2] was prepared from 16.3 g. (0.03 mole) of N,N-bis-[6-(4-cyclohexy1methyl-l-piperidyl) hexyl]amine and 5.55 g. (0.036 mole) of 1,2-cyclohexanedicarboxylic anhydride in about ml. of benzene using the manipulative procedure described above in Example 135. The product was isolated in the form of the dihydrochloride salt and the latter recrystallized from acetone to give 6.1 g. of N-(Z-carboxycyclohexylcarbonyl) N,N bis-[6-(4-cyclohexylmethyl-1-piperidyl)hexyl] amine dihydrochloride, M.P. 235.0235.5 C. (corr.).

EXAMPLE 140 1 -piperidyl)pr0pyl]amine dihydrochloride [1: R is 4-CH C H R3 is R4 is Y is 2)3; is

N cinnamoyl-N,N-bis- 3 4-cyclohexylmethyl- 1 -piperidyl)propyl]amine (12.6 g., 0.026 mole) was dissolved in about 200 ml. of absolute ethanol and reduced over 1.0 g. of palladium-on-charcoal catalyst under hydrogen at sixty pounds p.s.i. pressure. Reduction was complete in about two and a half hours, and the mixture was filtered from the catalyst, and the filtrate taken to dryness giving 11.4 g. of a pale yellow viscous oil. The latter was dissolved in 15 ml. of ether, and the solution treated with excess ethanolic hydrogen chloride. The solid which separated was collected, washed with ether and recrystallized from an ethanol/acetone mixture giving 8.9 g. of N (fi-phenylpropionyl) -N,N-bis-[3- (4-cyclohexylmethyl- 1-piperidyl)propyl]amine dihydrochloride, M.P. 257.5- 259.0 C. (corr.).

EXAMPLE 141 N-(B-phenylpropionyl)-N,N-bis-[6-(4-cycl0hexylmethyl 1 piperidyl)hexyl]amine dihydrochloride [I1 R is 4-CH C H R3 is R4 is Y is (CH n is 2] was prepared by catalytic reduction of 14.9 g. (0.02 mole) of N-cinnamoyl-N,N-bis-[6-(4-cyclohexylmethyl-l-piperidyl)hexyl]amine in 200 m1. of ethanol over 1 g. of palladium-on-charcoal catalyst using the manipulative procedure described above in Example 140. The crude product, converted to the dihydrochloride salt, was recrystallized from an ethanol/ acetone mixture giving 9.1 g. of N-(B-phenylpropionyl)-N,N-bis-[6(4-cyclohexylmethyl 1 piperidyl)hexyl]amine dihydrochloride, M.P. 185.8187.6 C. (corr.).

EXAMPLE 142 N-(fl-acyclohexylpropionyl)-N,N bzls' [3,(4 cyclohexylmethyl-1 -piperidyl) p'ropyl [amine dihydrochloride (1: R2 is 4-CH2C6H11; R3 is R4 is C H CH CH CO; Y is (CH n is 2] N-cinnamoyl-N,N- bis [3 (4 cyclohexylmethyl-l- 21 piperidy1)propyl]amine (9.9 g., 0.015 mole), dissolved in 200 ml. of absolute ethanol, was reduced over 1.0 g. of platinum oxide catalyst under hydrogen at a pressure of about 60 pounds p.s.i. and 60 C. Reduction was completed in about eight hours, and the reaction mixture was filtered from the catalyst, the filtrate diluted with 250 ml. of acetone and cooled. The solid which separated was collected, washed with ether and recrystallized from an ethanol/acetone mixture giving 9.3 g. of N-(fi-cyclohexylpropionyl) N,N-bis- [3 -(4-cyclohexylmethyl-1-piperidyl)tpropyl] amine dihydrochloride, M.P. 236-240" C. (corr.).

EXAMPLES 143-146 The following N-(fl-cyclohexylpropionyl) N,N-bis- (4-cyclohexylmethyll-piperidyl) -lower-alky-l] amines of Formula I (R is 4-CH C H R is H; R; is

n is 2) listed below in Table 9 Were prepared by reducing over platinum oxide the corresponding N-cinnamoyl- N,N-bis-[(4-cyclohexyl methyl 1 piperidyl) -loweralky-lJamines using the manipulative procedure described above in Example 142.

22 EXAMPLE 147 N-benzyl-N,N bis-[3-(4-cycl0hexylmethyl-1-piperidyl) propyljamine [1: R is 4-CH C H R is H; R; is C H CH Y is (CH n is 2] To a slurry of 0.38 g. (0.01 mole) of lithium aluminum hydride in 30 ml. of tetrahydrofuran was added, over a period of about forty-five minutes, a solution of 5.7 g. (0.01 mole) of N benzoyl N,N bis[3 (4-cyclohexylmethyl-1-piperidyl)propyl] amine, in 30 ml. of tetrahydro furan. The mixture was refluxed for five hours, allowed to stand overnight at room temperature, hydrolyzed by dropwise addition of a solution of 0.8 ml. of water in about 10 m1. of tetrahydrofuran and filtered. The filter was Washed With ether, the filtrate taken to dryness, and the residue recrystallized from acetone giving 3.1 g. of N-benzyl-N,N-bis-[3-(4-cyclohexylmethyl l-piperidyl) propylJamine, M.P. 36.840.2 C. (corn).

EXAMPLES 148-196 TABLE 9 The fOllOWlng N-(R )-N,N-b1s-[(4-cycl0hexylmethyl- 25 1-p1per1dyl)-lower alkylJamrnes of Formula I [R is Example Y Base or M.P. C.) Cryst.from 4-CH C H R 15 H; 11 1S 2] listed below in Table 10 Salt were prepared by reduction of the corresponding N-(RQ- amides with lithium alumlnum hydride using the manip- 2H)! 229'5 23m gfg gfifilf ulative procedure described above in Example 147. All (0H2); 2HC1 211. 0-214.0 Ethanol/acetone. 3O 0 e d 145..- cum 2HO1 ism-184.0 Ethanol/acetone/ether. meltmg Poms a e c n Cte 146 (CH1); 215101 195-197 Ethanol/ether.

TABLE 10 Exam 1e Y R Base or M.P. Cryst. fromp Salt 0.)

(011m CaHsCHz 31101 265. 0-268. 4 Methauol/acetone/ether. (0111) 2-01C6H1CH2 Ethggnol/acetone.

. 0. (CHM 401002140 2 163. 8-166 0 Methanol/acetone. (CHM 3,4-012CQH3CH2 3HC1 248.5-253 0 Ethanol/acetone. (CH2)3 4-CH3O CaH4CHz Base 33. 8-36. 8 Acetone. (0H2)s 4-CH3O 051140112 31101 217. 2-218. 6 Methanol/acetone. (CH 3-CF3C5H CH1 3H C1 285. 8-287. 6 Isopropanol/acetone/ether. (CI-1m 4-GF3C6H4CH; BHCI 246. 8-250. 4 Ethanol/acetone/ether. cum (OHaMOHCHz 31101 231. 0-233. 8 Do. ((1111):; CH3(CH2)4 lIllfltlgl'lolllalcetotne.l th

. -2 e ano ace onee er. (05K) GHKwHm 159.0-162.8 Acetone. (CH (OH3)2OHGH2CHZ 162. 0-164. 0 Methanol/acetone. (CH2 1 CH3(CH2)4 31101 239. 0-241.0 Ethanol/acetone. (CH 0 CH;(CH )5 160.0-162.0 Methanol/acetone. (CH M; CH;(CHz)e BHCI 260. 8-266. 4 Ethanol/acetone.

CH2)? CH3(CH)0 315101 257. 0-259. 6 Methanol/acetone. (CH C3H CH3 BHCI 282. 0-282. 4 Ethanol/acetone. (OH2)3 C4H7CH-z 3HG1 279. 6-280. 4 D0. (0112):: 0611110115 2HC1 285-287 Methanol/acetone. (CH2) 0 CGHH CH2 31101 262. 0-262. 6 Ethanol/acetone.

0112):: CcHsOCHzCH; Base 34. 4-35. 6 Acetone. (CHM 001150 GHZGHZ 31101 200. 0 Methanol/acetone/ether.

CHM -CHzCHx- Base 43. 6-44. 8 Isopropauol/acetone. (0112) (CH;)4 GHCI 291. 0-294. 0 Methanol/acetone. (CHM C2115 3HC1 300.0 D0. 2M z s 3H Cl 300. 0 Methanol. (CHm (4H 31101 284. 0-284. 8 Methanol/acetone. (CHM C2115 BHCI 291.2-293 0 Ethanol. (CH2)7 C2115 3HC1 249. 8-252 2 Do. (CH2): Cal-I1 3HC1 273. 4-274 0 Ethanol/acetone. (C1194 03111 31101 287. 2-288 8 Isopropanol/acetone. (CHM C3111 3HC1 260. 8-264 0 Ethanol/acetone/ether.

CHM 04119 31101 2826-283 6 Ethanol/acetone. (CI-I95 C4119 31301 255. 0-257 0 Do. (OHM C4Hn 3HC1 236.8-244 0 Methanol/acetone. (0112)! 4119 3HC1 229. 0-231 0 Methanol/acetone/ether. (CHm (OI-104011 31101 235. 0-238 0 Methanol/acetone. (CHM (CHmOH 31-101 249. 0-251 6 Ethanol/acetone.

CHM CsH5(CHz)a 3HC1 287. 4-288 5 D0. (CHM CaH5(CH2)3 31101 254.0-256 0 Do. (0119a 00 11(0 Base 578-60 0 Acetone. (0112M CeHu(CHz)3 BHOl 279. 2-281. 0 Ethanol/acetone. (OH2)5 CsHu(C 8HC1 281. 0-281. 4 D0. (CH2)0 CuHulCI-Iz): 3HC1 274. 0-277. 0 D0. (CH2)! CaH11(CH2)3 3H C1 261. 2-265. 0 ltiethanol/acetone. (CHM Z-HO OHBCGHIOOH: 3HC1 25?. 8-260. 0 D0. 2)a 2-NH2COH4CH2 198. 2-213. 0 Acetone. (CHM 4-NH O0H4OH: 41101 192. 0-200. 0 Methanol/acetone. (CH2); 2-HO C6H4GH: 3HC1 275. 0-296. 8 D0.

Tris cyclohexanesulfamate salt.

23 EXAMPLE 19 7 N-methyl-MN-bis-[3 -(4-cyclohexylm1ethyl 1 piperidyl) prpyl1amrine [1: R is 4-CH C H11; R is H; R, is CH Y is (CH n is 2] A solution of 13.8 g. (0.03 mole) of N,N-bis[3-(4- cyclohexylmethyld-piperidyl)propyl]amine in 5 ml. of formic acid was treated with 2.8 ml. (about 0.03 mole) of aqueous formaldehyde. When the initial vigorous reaction had subsided, the mixture was heated on a steam bath for about eight hours. A slight excess of concentrated hydrochloric acid was added, heating was continued for another five hours, and the mixture was basified with aqueous sodium hydroxide and extracted with chloroform. The combined chloroform extracts were taken to dryness and the residue recrystallized from a hexane/ acetone mixture giving 5.8 g. of N-methyl-N,N-bis-[3- (4-cyclohexylmethyl 1 piperidyl)propyl] amine, M.P. 40.8-41.8 C. (corr.).

EXAMPLES 198-201 The following N-methyl-N,N-bis[ (4-cyclohexylmethyll-piperidyl)-lower-alkyl]amines of Formula I [R is 4-CH C H R is H; R; is CH n is 2] listed below in Table 11 were prepared using the manipulative procedure described above in Example 197 by reacting the corresponding N,N-bis-[(4-cyclohexylmethyl-1-piperidyl)- lower-alkyl]amine with formaldehyde in formic acid. All melting points are corrected.

TABLE 11 Example Y Base or M.P. C.) Cryst. from- Salt 198 (OI-I04 3HC1 300.0 Ethanol/acetone. 199 (OI-12).; 31-101 299.8-301.8 Methanol/acetone. 200 (OHM 3HCl 300.0 Isopropanol/acetone 201 (CH-.01 Base 53.2-54.6 Methanol/acetone.

EXAMPLE 202 [3-{N,N-bis-[3 (4 cyclohexylmezhyl-l-piperidyl)propyl] amino}propio namiidoxime. [1: R is 4-CH C H R is H; R, is CH CH C (=NOH)NH Y is (CH m is 2] EXAMPLE 203 3-(4-cycl0hexylmelhyl 1 piperidyl)p'ropylguanidine hydrobromide [1: R is 4-CH C H11; R is H; R; is C(==NH)NH Y is (CH;);;; n is 1] A mixture of 4.76 g. (0.02 mole) of 3-(4-cyclohexy1- methyl-1-piperidyl)propylamine and 3.6 g. (0.02 mole) of 2-methyl-2-thiopseudourea hydrobromide, in about 15 ml. of absolute ethanol, was heated under reflux for about five hours and taken to dryness giving 6.3 g. of a pale yellow gum. The latter was recrystallized several times from acetone giving 3.5 g. of 3-(4-cyclohexylmethyl-1- piperidyl)propylguanidine hydrobromide, M.P. 112.0 113.0 C. (corr.).

EXAMPLE 204 N-(2-cyan0elhyl)-N,N bis [3-(4 cyclohexylmelhyl- 1-piperidyl)pr0pyl]amine [1: R is 4-CH C H R is H; R is CH CH CN; Y is (CH n is 2] A mixture of 13.8 g. (0.03 mole) of N,N-bis-[3-(4- cyclohexylmethyl-l-piperidyl)propyl] amine and ml. of

acrylonitrile was heated under reflux for about seven hours and taken to dryness in vacuo. The latter was recrystallized once from hexane and twice from acetone giving 11.7 g. of N-(2-cycloethyl)-N,N-bis[3-(4-cyclohexylmethyl-l-piperidyl)propyl]amine, M.P. 48.6-50.8 C. (corr.).

EXAMPLE 205 N-(2 hydroxyezhyl)-N,N-bis-[6-(4 cyclohexylmethyl- 1-piperidyl)hexyl]amine trihydrochlovide. [1: R is 4-CH C H R is H; R, is CH CH OH; Y is (CH n is 2] A mixture of 5.43 g. (0.01 mole) of N,N-bis-[6-(4- cyclohexylmethyl 1 piperidyl)hexyl]amine and 0.48 g. (0.01 mole) of ethylene oxide in ml. of dry benzene was heated in an autoclave at 124129 C. for eight hours and for an additional eight hours at -179" C. The reaction mixture was taken to dryness and the residual dark brown viscous oil was triturated with ethanol and a slight excess of ethanolic hydrogen chloride, slurried with acetone and the dark brown gummy solid collected and recrystallized several times from a methanol/ acetone mixture giving 4.6 g. of N-(2-hydroxyethyl)- N,N-bis-[6 (4 cyclohexylmethyl 1 piperidyl)hexyl] amine trihydrochloride, M.P. 276277 C. (corr.).

EXAMPLE 206 N-[N'-(2,4-dichl0rophenyl)thiocarbamyl] N,N bis-[6- (4-cyclohexylm ethyl 1 piperidyl)hexyl]am ine dihydrochloride [1: R is 4-CH C H R is H; R; is 2,4-(Cl C H )NHCS; Y is (CH n is 2] To a solution of 2.55 g. (0.03 mole) of 2,4-dichlorophenylisothiocyanate in about 30 ml. of benzene was added 5.43 g. (0.01 mole) of N,N-bis-[6-(4-cyclohexylmethyl-l-piperidyl)-hexyl]amine, and the mixture was allowed to stand at room temperature for about a half hour. The mixture was then treated with 3 ml. of ethanolic hydrogen chloride, diluted first with acetone, and then with ether, and the gummy solid which separated was collected and recrystallized several times from an isopropanol/acetone mixture giving 6.2 g. of N-[N-(2,4- dichlorophenyl)thiocarbamyl] N,N bis-[6 (4-cyclohexylmethyl 1 piperidyl)hexyl]amine dihydrochloride, M.P. 253.0 C. (corr.).

EXAMPLES 207-21 1 points are corrected. 7

TABLE 12 Example Y R4 M P. C Crystd.

from- O H NHCO 76. 4-77. 2 Acetone. CpI'IllNHCO 86. 8-88. 2 Do. CH (CH2)3NHCO 83. (P84. 5 D0. GH (GHi)sNHOO 60. 4-61. 4 Do. 225. 0 Methanol.

A mixture of 10.5 g. (0.02 mole) of N,N-bis-[6-(4- cyclohexylmethyl-1-piperidyl)hexyl]amine and 50 ml. of

EXAMPLE 213 N (4 nitrobenzyl)-N,N-bis-[6-(4wyclohexylmetlzyl-1- piperidyl)-hexyl]amine trihydrochloride [1: R is 4-cH2C5 11; R3 is H; R4 is 4-N02C6H4CH2; Y is (CH2)6; n is A mixture of 5.43 g. (0.01 mole) of N,N-bis-[6-(4- cyclohexylmethyl-1-piperidyl)hexyl]amine, 2.55 g. (0.015 mole) of 4-nitrobenzyl chloride, and 2.12 g. (0.02 mole) of sodium carbonate in 70 ml. of absolute ethanol was heated under reflux for four hours. The mixture was taken to dryness, the residue dissolved in a benzene/ether mixture, the organic solution decanted from the solid residue and extracted with dilute hydrochloric acid. The aqueous layer of the resulting three-phase system was discarded, and the middle layer was dissolved in chloroform, extracted with sodium bicarbonate, washed with Water, dried and taken to dryness. The residual orange gum was dissolved in a small amount of ethanol and treated with an excess of ethanolic hydrogen chloride. Dilution of the mixture with ether alforded the crude product in solid form which was collected and recrystallized from methanol giving 2.7 g. of N-(4-nitrobenzyl)-N,N-bis- [6-(4-cyclohexylmethyl-1-piperidyl) hexyl]amine trihydrochloride, M.P. 231.0-233.0 C. (corn).

EXAMPLE 214 N (Z-aminobenzoyl) -N,N-bis-[3-(4-cyclohexylmethyl-1- piperidyl)propyl]amine trihydrochloride [Iz R is 4-CH2C5H11; R3 is H; R4 is 2-NH2C6H4CO; Y is 2)3; n is A mixture of 11.6 g. (0.02 mole) of N,N-bis-[3-(4- cyclohexylmethyl-1-piperidyl) propyl1amine and 4.4 g. (0.03 mole) of isatoic anhydride in about 100 ml. of benzene was heated under reflux for three hours and then taken to dryness. The residue was dissolved in 200 ml. of methanol, cooled overnight in a cold room, and the solid material which separated was collected to give 6.1 g. of N-(2-carboxyphenylaminocarbonyl) N,N-bis-[3- (4-cyclohexylmethyl-1-piperidyl)propyljamine as a byproduct. Concentration of the filtrate to a small volume and further cooling afiorded a second crop of 1.0 g.'of the same by-product.

The filtrate obtained after collection of the abovenamed by-product was concentrated to a small volume,

acidified with 6.0 m1. of 7.33 N ethanolic hydrogen chloride, diluted strongly with ether, salt which separated was collected g. of crude material.

The latter was dissolved in chloroform and reconverted to the free base by washing with dilute sodium carbonate and water and drying the chloroform solution containing the free base over anhydrous calcium sulfate. The solution was then rendered 2% in isopropylamine by addition of 6.0 ml. of the latter and treated three times with stirring for fifteen minutes with 5.0, 10.0, and 15.0 g. batches of silica gel, filtering the solution each time from the adsorbent. I

The solution was then taken to drynessonce again, the residue was dissolved in absolute ethanol, and the solution acidified with excess ethanolic hydrogen chloride. Dilution of the solution with acetone and ether caused the separation of a solid material which was collected and recrystallized from isopropanol/acetone to give 3.4 g. of N-(Z-aminobenzoyl)-N,N-bis-[3-(4-cycloand dried to give 7.2

and the hydrochloride 26 hexylmethyl-1-piperidyl)propyl]amine M.P. 240.0-260.0 C. (indef., corn).

EXAMPLE 2 15 N (4 nitrobenzoyl) -N,N-bis-[6-(4-cyclohexylmethyl- 1-piperidyl)hexyl]amine dihydrochloride (10.8 g., 0.014 mole) was dissolved in 250 ml. of absolute ethanol and reduced over 0.2 g. of platinum oxide catalyst under an initial hydrogen pressure of 60 pounds p.s.i. at room temperature. After an uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration, and the filtrate evaporated to a volume of about 50 ml. The solid which separated on cooling was collected and dried giving 3.2 g. of N-(4-aminobenzoyl)-N,N-bis-[6-(4-cyclohexylmethyl 1-piperidy1)hexyl] amine dihydrochloride, M.P. 241.6243.0 C. (coma).

EXAMPLE 216 N (3,5 diaminobenzoyl) N,N bis-[6-(4-cyclolzexylmethyl J piperidyl)hexyl]ami'ne dihydrochloride [1: R2 is 4-CH2C5H11; R3 is H; R4 is 3,5-(NI'I2)2C6H3CO; Y is (CH n is 2] N (3,5 dinitrobenzoyl) N,N-bis [6 (4 cyclohexylmethyl 1 piperidyl(hexyl] amine dihydrochloride (19.1 g., 0.024 mole) Was dissolved in 250 ml. of ethanol and reduced over 0.6 g. of platinum oxide catalyst under an initial hydrogen pressure of 60 pounds psi. and at a temperature of from 28 to 42 C. After a total uptake of the theoretical amount of hydrogen, the catalyst was removed by filtration, and filtrate evaported to a small volume and cooled. The solid which separated was collected and dried giving 5.5 g. of N-(3,5-diaminobenzoyl)- N,N bis-[6-(4-cyclohexylmethyl-1-piperidyl) hexyl]amine dihydrochloride, M.P. 250.0252.0 C.

EXAMPLE 21 7 N (3 amino 4 chlov'obenzoyl) N,N bis [6 (4 cyclohexylmethyl l piperidyl).hexyl]amine dihydr0 chloride [I: R is 4-CH C H R is H; R; is 3-NH 4-ClC H CO; Y is (CH n is 2] N 3 nitro 4 chlorobenzoyl) N,N bis [6 (4 cycl-ohexylmethyl-lapiperidyDhexyllamine dihydrochloride (21.7 g., 0.03 mole) was dissolved in 250 ml. of absolute ethanol and reduced over 0.6 g. of a platinum oxide catalyst at an initial hydrogen pressure of 60 pounds psi. at room temperature. After a total uptake of the theoretical amount of hydrogen, the catalyst was removed by filtra tion, and the filtrate taken to dryness. The residue was recrystallized several times from a methanol/acetone/ ether mixture and once from acetone alone giving 3.4 g. of ,N (3-amino 4 chlorobenzoyl) N,N-bis-[6-(4- cyclohexylmethyl 1-piperidyl)hexyl]amine dihydrochlotrihydrochloride,

ride, M.P. 205.4207.6 C. (corn).

EXAMPLE 218 N (4 acetylaminobenzoyl) N,N bis [6 (4 cycl0- hexylmethyl 1 piperidyl) hexyflamine dihydrochloride [I: R is 4-CH C H11; R is H; R; is 4- CH CONHC H CO; Y is (CH n is 2] give 5.4 g. of N-(4-acetylaminobenzoyl)-N,N-bis-[6-(4- 27 cyclohexylmethyl 1 piperidyl)hexyl]amine dihyd-rochloride, M.P. 185.0189.0 C. (corr.).

EXAMPLE 219 N (3, diacetylaminobenzoyl) N,N bis [6 (4 cyclohexylmethyl 1 piperidyl)hexyl]amine dihydrochloride R2 4-CH2C6H11; R3 iS R4 is 3,5-(CH CONH) C H CO; Y is (CH n is 2] stallized from an isopropanol/ acetone mixture giving 3.9 g. of N-(3,5-diacetylaminobenzoyl)-N,N-bis-[6-(4- cyclohexylmethyl 1 piperidyl) hexyl]amine dihydrochloride, M.P. 2250-2260 C. (corn).

EXAMPLE 220 N (N,N' diethylaminocarbonyl) N,N bis [6 (4- cyclohexylmethyl 1 piperidyl)hexyl1amine [1: R is 4CH2C6H11; R3 is R4 is Y is (CH n is 2] By reacting N,N-bis [6 (4 cyclohexylmethyl 1 pi-peridyl)hexyl]amine with N,N-diethylcarbamyl chloride in the presence of sodium carbonate, there can be obtained N (N',N' diethylaminocarbonyl) N,N bis [6 (4 cyclohexylmethyl 1 piperidyl)hexyl]amine.

EXAMPLES 221-225 By following the manipulative procedure described above in Example 220 substituting for the N,N-diethylcarbamyl chloride used therein a molar equivalent amount of N,N-diethylthiocarbamyl chloride, piperidinocarbonyl chloride, pyrrolidinocarbonyl chloride, piperidinothiocarbonyl chloride, or pyrrolidinothiocarbonyl chloride, there can be obtained the respective compounds of Examples 221-225 listed below in Table 13 where, in each case R2 is 4CH C H R3 iS Y is and n is I 28. EXAMPLE 226 4 {3 [4 (N mvethylcarbamyl) 1 piperidyflpropylamino} 7 chloroquinoline [1111: R is 7-Cl; R is 4CONHCH R is H; Y is (CH n is 1] A mixture of 11.9 g. (0.06 mole) of 4,7-dichloroquinoline, 17.9 g. (0.09 mole) of 3-[4-(N-methyl- I carbamyl)-1-piperidyl1propylamine, and 35 g. of phenol was heated with stirring at 115125 C. for twenty-four hours. The mixture, while still warm, was dissolved in 300 ml. of chloroform and the solution extracted with three ml. portions of 10% hydrochloric acid. The combined acid extracts were basified with concentrated ammonium hydroxide, extracted with chloroform, and the chloroform extracts dried over Drierite and taken to dryness. The residue was dissolved in 10% acetic acid, filtered and the filtrate basified with concentrated ammonium hydroxide. The brown gum which separated was washed by decantation with water, triturated with ethyl acetate and the resulting solid was collected and recrystallized from an ethanol/ethyl acetate mixture giving 9.4 g. of 4 {3 [4 (N methylcarbamyl) 1 piperidyl]- propylamino} 7 chloroquinoline, M.P. 174.8175.4 C. (corn). EXAMPLES 227-232 The following compounds of Formula IIa listed below in Table 14 were prepared according to the manipulative procedure described above in Example 226, using 4,7-dichloroquinoline and an appropriate monoor bis-[(1-piperidyl)-propyl]amine. In each case R is 7-Cl, R is H, and Y is (CH All melting points are corrected.

TABLE 14 Example R2 n M P. C C Cryst. from 4-CONH1 1 217. 4-219. 6 Ethanol/ethyl acetate.

. 4-CONHC2H5... 1 188. 2188.8 Do.

4-CON(CH3)2 1 187. 2188.4 Acetone.

4-CON(C H5)Z 1 140. 0-140. 6 Ethyl acetate/hexane. 4-CONHCH3 2 164. 0165.0 Ethanol/ethyl acetate.

4CONHC2H5. 2 165. 4-1602 D0.

EXAMPLES 23 3-25 6 By following the manipulative procedure described above in Example 226, substituting for the 4,7-dichloro- TABLE 13 quinoline and the 3-[4-N-methylcarbamyl)-1-piperidyl] Example: R propylamine used therein, molar equivalent amounts of 221 (C H NCS an appropriate 4-halo-substituted-quinoline and an appro- 222 C H NCO 50 priate monoor bis-[(substituted-l-piperidyl)-lower- 223 C H NCO al'kyl] amine, there can be obtained the 4-{monoor his- 224 C H NCS [(substituted 1 piperidyl) lower alkyl] amino}-substi- 225 C H NCS tuted-quinolines of Formula Ila listed below in Table 15 TABLE 15 Example Y/Ri Rz/Ra n 233 (CH2); 4-CH2OH 1 5-CH30 234 (oHm 4-CH2OHZOHZOH 1 7-CH3S 235 (CH2)2 4-110 1 7-OH3S0 2,6-di-CHa 236 (0112):; 4-HO 1 7-CH3SO2 2,2,4,6,6-penta-CHa 237 OHm 4-H 1 743611501 2,2-di-cH -6-(oH )2011011 238 a- (CH2)3 4-(CH2)0OH 1 7-(4- louHicHzo) s 239 (CH2); 4-NHOH0 1 7-(4-HOC5H4CH20) 240 (OHm 4-NHCOCH(C2H )OH2OH l" '7 7-(3,4-OCH2OCBH3CHQO) 241 011m 3-CONHCH2CH2CH2CH3 1 7-(3-CH3CBH4CH20) 242 oHm 4-OONH2 1 7-(3-CH3SO2CEH4CHZO) 243 (CH2); 4-CONH 1 244 (o in); i-'omot-nu 2 5CH3O 245 (CHm 4-CH OII 2 7-CH3S TABLE -C0ntinued Example Y/Ri Ri/Rs 11 251 (C119 l-NHCHO 2 7-(3A-OCH OCsHgCHgCIFhO) 253 (CH2 3-CONHCH CH2CH2CH3 2 7'(2'C:EI3OCBH4CH2CH20) 254 (CH2); 4-CONH2 2 EXAMPLE 257 used therein, molar equivalent amounts of an appropri- 2- [3 -(4-carbamyl-1 -piperidyl propylamino] qwinoli'ne [Hbz R is H; R is 4-CONH R is H; n is 1] By reacting 2-chloroquinoline with 3-(4-carbamyl-1- piperidyl)propylamine according to the manipulative procedure described above in Example 226 there can be obtained 2-[3-(4 carbamyl 1 piperidyl)propylamino] quinoline.

EXAMPLES 258271 By following the manipulative procedure described above in Example 226, substituting for the 4,7-dichloroquinoline and the 3-[4-(N-methylcarbamyl)-1-piperidyl] propylamine used therein, molar equivalent amounts of an appropriate 2-halo-substituted-quinoline and an appropriate (substituted-l-piperidyl)-l0Wer-alkylamine, there can be obtained the 2-[(substituted-l-piperidyl)alowen alkylamino]-substituted-quinolines of Formula 11b (n is 1) listed below in Table 16:

TABLE 16 Ex. Y/Ri z/ s s-- gal -I2): 4-CONHOH3 259.... b 1512 iio'oNrroim 7. 260.- %I1I2)a 4CON(CH3)2 261,. ugs; io'omoinm 2s2 (or-rm lomorr 5'CHs0 263 (CH2): 4-CH2CHaOH2OH 7-CHQS 2s4 (0H2); 4-110 7-011 2,6-di-OH; 265 (C119 4-HO 7-CHaSO 2,2,4,6,6-penta-CHa 266"" (CH2); 4-HO 7436111 011 0 2,2-di-CH3-6-(CE[3) 2oHOH2 267.-.- (OI-rm 4-(OHmOH 7(4-C1CISH4OH20) 268 (01123 A-NHCHO 7-(4-I-IOC0H4CH2O) 269 (CH2); 4-NHCOCH(C2H5)CH2CH3 l 7-(S.4WC6H3CH2O) 270 (01193 3-CONHCH2CII2CH2CH3 7-(3-oH30BHi0H 0) 271 (CHm 4-OONH2 7-(3-CII3SO2C6H4CH20) EXAMPLES 272-286 By following the manipulative procedure described above in Example 226 for the 4,7-dichloroquinoline and the 3-[4-(N-methy1carbamyl) 1 piperidyHpropylamine ate 2-halo-substituted-quinoline and an appropriate bis- [(substituted-l-piperidyl)-loweralkyl]amine, there can be obtained the 2-{bis-[(substituted-1-piperidyl)-lower-alkyl] amino}-substituted-quinolines of Formula III) (is is 2) listed below in Table 17:

Our new l-piperidyl)-lower-alkylamines of Formula I showed anti-inflammatory activity in one or more of three diiferent test procedures, viz, inhibition of granulorna pouch formation in rats, inhibition of dextran-induced local foot edema in rats, and inhibition of para-influenza (Sendai strain) virus-induced lung inflammation in mice. Data obtained for representative compounds of the series are given in Table 18 which follows. The activities are given in terms of the minimum dose (MIND) which is defined as the smallest dose producing 30% inhibition of the inflammation in the lung infiammation and dextran edema tests and 40% inhibition in the granuloma pouch test. The symbols G.P., LL, and DE. represent the tests named above, namely the granuloma pouch, lung inflammation, and dextran edema tests, respectively, while the designations so. and p0. represent subcutaneous and peroral routes of administration, respectively.

TABLE 18 Example GI L.I. D.E

25 (p.o.) 1.56 (5.0) 1.56 (5.0.) (p.o) 100 (p.o.) 1.56 (5.0.) 100 (5.0) 0.4 (5.0.) 25 (p.o.) 0.40 (5.0.) 1.56 (5.0.) 1.56 (5.0.) 0.10 (5.0.) 1.56 (5.0.) 100 (p.o.) 0.10 (5.0.) 0.10 (5.0.) 6.25 (5.0.) 6.25 (p.o.) 0.40 (5.0.) 6.25 (5.0.) 1.56 (5.0.) 6.25 (5.0.) 25 (p.o.) 6.25 (5.0.) 6.25 (5.0.) 6.25 (5.0.) 1.56 (5.0.) 6.25 (5.0.) 100 (p.o.) 100 (p.o.) 100 (p.o.) 6.25 (5.0.) 6.25 (5.0.) 100 (p.o.)

6.25 (5.0.) 6.25 (5.0.) 100 (p.o.) 100 (p.o.) 100 (5.0.) 25 (5.0.) 6.25 (5.0.) 25 (5.0.) 25 (5.0.) 6.25 (5.0.) 100 (p.o.) 25 (5.0.) 25 (5.0.) 25 (5.0.) 6.25 (5.0.) 25 (5.0.)

p.o. 0.25 (5.0.) 6.25 (5.0.) 100 (p.o.) 0.40 (5.0.) 6.25 (5.0.) 6.25 (5.0.) 25 (5.0.) 100 (p.o.) 6.25 (5.0.) 100 (p.o.) 1.56 (5.0.) 1.56 (5.0.) 6.25 (5.0.) 6.25 (5.0.) 25 (p.o.) 1.56 (5.0.) 100 (p.o.) 0.40 6.25 (5.0.) 100 (p.o.) 0.10 (5.0.) 6.25 (5.0.) 1.56 (5.0.) 0.40 (5.0) 1.56 (5.0.)

(p.0. 25 (p.o.) 0.10 (5.0 6.25 (5.0.)

(p.o. 25 (p.o.) 1.56 (5.0.) 0.40 (5.0.) 1.56 (5.0.)

(p.o. 6.25 (p.o.) 6.25 (5.0.) 0.40 (5.0.) 6.25 (5.0.) 6.25 (p.o.) 25 (p.o.) 1.56 (5.0.) 25 (p.o.) 6.25 (5.0.) 0.40 (5.0.) 25 (p.o.) 6.25 (5.0.) 1.56 (5.0.) 0.40 (5.0.) 0.40 (5.0.) 0.40 (5.0.) 1.56 (5.0.)

25 (p.o.) 100 (5.0.) 100 (p.o 25 (5.0.)

In addition to having anti-inflammatory activity, our new (l-piperidyl)-lower-alkylamines showed hypotensive activity in renal hypertensive rats. Data, expressed either in terms of the Average Effective Dose (AED) or the Minimum Effective Hypotensive Dose (MEHD), so-obtained for representative compounds in the series are given in Table 19 below.

TABLE 19 Example Activity 33 MEHD=1.0 dig/kg. (5.0.). 35 MEHD=1.0 mg./l g. (5.0.). 39 AED=9O mg./kg. (5.0.). 62 AED=40 mg./kg. (5.0.). 63 AED=3 rug/kg. (p.o.). 64 AED=4O mg./kg. (5.0.). 65 AED= mg./kg. (p.o.). 69 AED=15 mg./kg. (s.c.). 70 AED=2 mg./kg. (5.0.).

71 AED=50 mg./kg. (p.o.). 202 AED=6 mg./kg.. (s.c.).

The compounds of the Formula I have also been shown to possess coronary dilator activity when tested in the isolated rabbit heart. Coronary dilator activity data soobtained for representative compounds of the series are given in Table 20 below. The activities are expressed either in terms of the Effective Dose (ED or in terms of the percent dilatation, at a given dose level, the doses inboth cases being expressed in terms of the dose per heart.

TABLE 20 Example Activity 32 1.8% dilatation at 0.1 mg.

42 ED =87 meg; 164% of papaverine.

44 ED SO mcg.; 284% of papaverine.

47 ED =33.5 mcg.; 424% of papaverine.

62 24.7% dilatation at 0.05 mg.

69 ED =90 mcg.; 63%of papaverine.

71 41% dilatation at 8 mcg.

89 ED =6.1mcg.;2328% of papaverine.

90 25% dilatation at 50 meg.

102 23% dilatation at 50 mcg.

153 ED =10.8 mcg.; 1315% of papaverine.

154 12% dilatation at 50 mcg.

164 13% dilatation at 50 mcg.

169 12% dilatation at mcg.

172 ED =6.6 mcg.;2152% of papaverine.

173 19% dilatation at 100 mcg.

178 34% dilatation at 100 mcg.

179 ED =S.7 meg; 2500% of papaverine.

180 ED =4.2 mcg.; 3380% of papaverine.

181 ED =8.2 mcg.; 1732% of papaverine.

182 ED =10.1 mcg.; 1420% of papaverine.

197 21% dilatation at 50 mcg.

The compounds of Formula I have also been shown to have tranquilizer activity as determined in mice using.

standard activity cages. Tranquilizer activity data so-obtained for representative compounds of the series are given below in Table 21. The data are given in terms of the percentage decrease in the animals activity at a particular dose level.

89 59% decrease at 300 mg./kg. (p.o.)

33 Example Activity 90 76% decrease at 16 mg/kg. (p.o.) 172 71% decrease at 100 mg./kg. (p.o.) 173 90% decrease at 300 mg./kg. (p.o.) 177 58% decrease at 100 mg./kg. (p.o.) 178 75% decrease at 100 mg./kg. (p.o.) 179 -Q 76% decrease at 100 mg./kg. (p.o.) 181 86% decrease at 300 mg./kg. (p.o.) 182 71% decrease at 300 mgQ/kg. (p.o.) 197 71% decreases at 300 mg./kg. (p.o.) 198 69% decrease, at 10 mg./kg. (p.o.) 199 65% decrease at 100 mg./kg. (p.o.) 201 72% decrease at 300 mg./kg, (p.o)

The Average Efiective Dose (AED of 4- N,N- possess anthelmintic activity when administered orally to Swiss mice .infectedlby the tapeworm, Hymenolepis nana, and the pinworm, Aspicularis tetraptera. Data so-obtained with representative compounds are given below in Table 22 and are expressed in terms of the dose, in mg./kg./day administered two times a day for four days, required to clear all of the animals in the test group of each of the test Organisms.

TABLE 22 Dose (mg./kg./day) Hy. nana Asp. tetraptera The compounds of Formula 11a and II!) have been shown to possess hypotensive, antimalarial, anthelmintic and Trichomonacidal activities. As representative of these various activities shown by these compounds are the following:

The Average Effective Dose (AED of 4- N,N- bis-{3 [4 (N-methylcarbamyl) 1-piperidyl1propyl} 34 amino -7-chloroquinoline, prepared above in Example 231 administered subcutaneously in. the renal hypertensive rat, was found to be about 10 mg./kg.; the AED of 4- {3 [4 (N,N-dimethylcarbamyl) 1 piperidyl1propylamino}-7-chloroquinoline, prepared above in Example 229, administered subcutnaeously in the renal hypertensive rat, was found to be 17.5 mg./kg.; 4-{3-[4-(N-methylcarbamyl)-1-piperidyl]propylamino}-7 chloroquinoline, prepared above in Example 226 tested against various species of the malarial parasite Plasniodium, was found to be effective at a dose level of 25 mg./kg./day; 4-{3-[4- (N,N-dimethylcarbamyl)-l piperidyl]-propylamino} 7- chloroquinoline, prepared above in Example 229, tested against the malarial parasite, Plasmodium lophurae, was found to be effective at a dose level of 10 mg./kg./day; and 4-[3-(4-carbamyl-1-piperidyl)propylamino]-7 chloroquinoline, prepared above in Example 227, tested against various species of the malarial parasite, Plasmodium, was found to be effective at a dose level of 20 mg./ kg./ day; 4-[3-(4-carbamyl 1 piperidyDpropylamino] '7- chloroquinoline, prepared above in Example 227, administered to Swiss mice infected With nematode, Syphacea obvelata, and the tapeworm, Hymenolepis nana, cleared 80% of the animals of the infections in both cases at a dose level of 200 mg./kg./day; and 4-{3-[4-(N-methylcarbamyl)-1-piperidyl]propylamino}-7-chloroquinoline, prepared above in Example 226, administered to Swiss mice infected with the tapeworm, Hymenolepis mum, and the nemtaode, Aspicularis tezraptera, cleared of the animals of the former infection and. of the animals of the latter infection at a dose level. of 400 mg./kg./day.

The compounds can be prepared for use by dissolving under sterile conditions a salt form of the compounds in Water (or an equivalent amount of a non-toxic acid if the free base is used), or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for intramuscular injection. Alternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, st-a-rch, lactose, talc, magnesium stearate, gum acacia, and the like. Still further the compounds can be formulated for oral administration in aqueous alcohol, glycol or oil solutions or oil-Water emulsions in the same manner as conventional medicinal substances are prepared. When used as hypotensive agents, they are formulated and used in the same manner as conventional hypotensive agents, such as reserpine preparations, and indeed can be used advantageously in combination with such hypotensive agents.

- We claim:

1. A compound of the formula wherein R is a member of the group consisting of unsubstituted carbamyl, N-lower alkylcarba-myl, N,N-diloWer-alkylcarbamyl, piperidinocarbonyl, py-rrolidin ocarbonyl, hydroxy, hydroxy-loWer-alkyl, lower-alkanoylamino, phenyl-lower-alkyl, and cycloalkyl-lower-alkyl; R is a member of the group consisting of hydrogen and from one to five loWer-alkyls; R is a member of the group consisting of carbamyl, N-lower-alkylca-rbamyl, N-cycloalkylcarbamyl, N,N-di-lower-alkylcarbamyl, N- phenylcarbamyl, piperidinocarbonyl, pyrrolidinocarbonyl, thiocarbamyl, N-lower-alkylthiocarbamyl, N,N-di-loweralkylthiocarbamyl, N-phenylthiocarbamyl, piperidinothiocarbonyl, pyrrolidinothi-ocarbonyl and dicarbamylbiphenyl; Y is loWer-alkylene; and n is the integers 1 and 2, the third valence on the amino nitrogen atom being attached to a hydrogen atom when n is 1.

3,325,500 35 36 2. A compound of the formula 5. N-(N'-p'henylcarbamyl) N,N-bis-[6-(4-cyc1ohexy1- methyl-l-piperidyl)hexyl]amine.

R2 1 i NYINR4 References Cited 2 5 UNITED STATES PATENTS wherein R2 is cycloalkyl-lower-alkyl; R4 is N-cycloalkyl- 2,203,504 6/1940, Piggott et a1. carbamyl; and Y 13 lower'alkylene- 2,762,842 9/1956 Hafiige-r et a1. 260-294 A compound of the formula 3,126,272 4/1964 Fischer et a1 2-60 294 10 OTHER REFERENCES N Y N R4 Theilheimer, Synthetic Methods of Organic Chemis- J try, V01. 8, Reactions 391 (p. 15-7 533 (p. 211 688 271 Kar N Y0 k, 1954. wherein R is cycloalkyl-lower-alkyl; R is N-phenylcar- (p ger cw r a y; is i g y 1) N N b. [6 (4 1 15 WALTER A. MODANCE, Primary Examiner. -cyc o exycar amy 1s- -cyc 0- y y p p dy h y D. Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,325,500 June 13, 1967 Bernard L. Zenitz et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent. should read as corrected below.

Column 3, line 31, for "pehnoxy" read phenoxy line 68, for "cyanpropyl" read cyanopropyl column 6, lines 53 and 54, for "hydrogent read hydrogen column 7, line 29, for "Formula" read"-"- Formula I column 9, line 59, for "hours" read hour"- -;c0lumn 10, line 3, for "crontonic" read crotonic' lines 11 and 12, for "hydrochloric acid, hydrochloric acid, hydrobromic acid," read hydrochloric acid, hydrobromic acid, column 13, lines 28 and 29, for "6-aminophenylarsinate'read p-aminophenylarsinate line 53, for "rhodimum" read rhodium column 13 and 14, TABLE 3, sixth column, line 5 thereof, for "Isoproponal" read Isopropanol--; column 14, line 31, for "n is 21" read n is 2 column 18, line 24, for "Examples 123-134" read Examples 124-134 column 22, line 26, for "R is H" read R is H columns 21 and 22, TABLE 10 opposite Example 166 third column, for "ZHCl" read 3HC1 column 26, line 29, for "(hexyl" read hexyl line 34, for "evaported" read evaporated line 44, for "Y is [CH read Y is (CH column 32, line 33, for "ED read ED column 33, line 14,

for "The Average Effective Dose (AED J of 4 N,N-" read The compounds of Formula I have also been shown to line for I Sd" read Column 34 11m 29, for

nemtaode read nematode".

Signed and sealed this 17th day of June 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA
 4. N - (N''-CYCLOHEXYLCARBAMYL) - N,N-BIS(6-(4-CYCLOHEXYLMETHYL-1-PIPERIDYL)HEXYL)AMINE. 